Summary Project 2 will test the hypothesis that despite their complexity and tortuous nature, the somatic evolution of B cells to bNAb activity is deterministic. That is, generation of bNAbs will follow a common and reproducible pathway(s) of clonal evolution that is reproducible in response to SHIV infections with chimeric viruses bearing Envs from primary or transmitted/founder HIV-1 strains. This question is crucial to the potential utility of all HIV- 1 lineage design vaccine strategies: if bNAb responses are unique accidents of somatic evolution, lineage design vaccines based on the response of a single, rare human subject are unlikely to be generally applicable. In contrast, if clonal evolution to bNAb activity in individual humans and in RMs follows a shared evolutionary trajectory guided by serial antigen exposure, lineage design vaccines that guide clonal evolution will be potentially effective in many vaccinees. Project 2 comprises three Specific Aims. In Aims 1 and 2, we propose to characterize the germinal center (GC) and memory B-cell (Bmem) responses in RMs identically infected in Project 1 with molecularly cloned SHIV-CH848 (or other V3-glycan targeting SHIV) or SHIV-CAP256 (or other V1V2 targeting SHIV). The principal goal of these studies is to determine whether the NAb and bNAb responses of different outbred RMs are substantially similar in a SHIV Env-specific manner. In collaboration with Cores B and C, we will define the specificity, avidity, neutralization capacity, and somatic genetics of NAb and bNAb B cells elicited by SHIV infection. Similar B-cell responses, as defined by specificity and V(D)J selection, will demonstrate that deterministic factors control the somatic evolution of NAb and bNAb B cells elicited by SHIV infection. In Aim 3, we propose to follow the B cell responses of SHIV infected RMs that have been vaccinated by Project 3. In the event that any vaccine does not confer full and complete resistance to infection, Aim 3 will allow us to characterize the vaccine's effects on clonal selection, affinity maturation, and changes in the frequencies of NAb and bNAb B-cell clones elicited by SHIV infection. This information will allow Project 3 to ?tune? vaccine strategies for maximal effect. 1